This application is a resubmitted R01 proposal in response to PA-09-097 Alcohol, Decision- Making, and Adolescent Brain Development (NIAAA). The project capitalizes upon an existing longitudinal sample of adolescents who were enrolled starting in 2004 in a longitudinal brain development study. Participants, ages 9 to 23, underwent an extensive structural neuroimaging protocol that included T1-weighted and diffusion-weighted scans, and also completed a comprehensive behavioral testing battery and a set of self- report questionnaires. Most participants were free of alcohol and drug use at study enrollment. Participants completed one follow-up assessment, two years after the baseline enrollment, using similar data collection methods as at baseline. [A third assessment wave was completed on approximately half the sample since this proposal was reviewed]. Here, funds are requested to conduct two additional longitudinal assessments of the full sample (n=170), many of whom have transitioned from no alcohol use to significant use over time. To date, found age-related improvements were found in numerous frontal lobe-mediated functions, including planning, delay discounting, inhibitory control, and motivated decision making. These functions are associated with white matter integrity throughout the brain, but particularly within tracts that connect the frontal lobe with striatal brain regions. Preliminary findings indicate that individuals who initiated alcohol use, and/or increased their use over time, showed signs of reduced white matter development, specifically with respect to fiber pathways that provide connectivity among cortical regions (superior parietal, anterior temporal, prefrontal) involved in high-level associative processes as well as inhibitory cognitive and behavioral control. Additionally, longitudinal effects of alcohol use include reduced volume of neural fibers connecting the key subcortical structure involved in mediating incentive-reward activation, the nucleus accumbens, with the key cortical region involved in providing descending inhibitory control over behavioral responses to reward cues, the medial orbitofrontal cortex. [Preliminary findings from the partial Time 3 data collection include reductions in white matter integrity of brain regions directly involved in memory processes (hippocampal gyrus, temporal polar cortex) in association with escalating alcohol use from Time 2 to Time 3.] Additional longitudinal assessment will permit a more sophisticated modeling, using linear mixed models, of the effects of adolescent alcohol initiation on ongoing neural connectivity development, together with parallel analyses on associations between behavioral and brain development and how alcohol initiation impacts them. Within the proposed study, the investigators will be able to assess brain connectivity via structural MRI, electrophysiology, resting state fMRI, and a broad range of behavioral tasks. Thus, this application meets NIAAA funding objectives, because the scientific inquiry into the question of alcohol's effects on the developing brain will be advanced. PUBLIC HEALTH RELEVANCE: This resubmitted application incorporates structural neuroimaging and neurocognitive assessment in a longitudinal study of adolescent brain development that focuses on indices of connectivity and how they change with alcohol use initiation and continued use. Information regarding various aspects of adolescent brain development, including changes in brain structure and associated behaviors, are important to parents of children with and without clinical disorders, to the general public and to public health initiatives (those related to substance abuse prevention;to the prevention of teen pregnancy;to health behavior in adolescents;to ages when privileged behaviors such as driving are allowed, for example), to education, to the legal community particularly in relation to juvenile justice, to developmental neuroscience, and to psychiatry. These constituencies touch virtually all of society. Thus, the relevance of the proposed research is broad in scope and may potentially change or refine society's conceptualizations of adolescent behavioral and brain development and how these typically change over time and are altered in the context of normative levels of alcohol use. [The thesis is that typical levels of adolescent alcohol use disrupt neural connections that undergo active development during this period, thereby establishing vulnerabilities for behavioral problems - including escalating alcohol use - in both the short and long term.]